The BCL‐2 Family Proteins – Key Regulators and Effectors of Apoptosis

Abstract

BCL‐2 was the first cloned component of the mechanism for apoptosis – the process by which metazoan cells commit suicide –
to be recognized. Mammals are now known to carry genes for a large number of BCL‐2 like proteins, some of which, like BCL‐2
itself, inhibit apoptosis, and others that promote or are required for apoptosis. Direct interactions between BCL‐2 family
members are essential for the proper regulation and implementation of apoptosis during development and for homoeostasis. Abnormalities
to the regulation of cell death, such as those caused by mutations to genes for BCL‐2 family members prevent apoptosis occurring
when it should, and can lead to diseases including cancer. Understanding the roles of BCL‐2 family members, their structures
and how they interact, has allowed the development of novel agents for the treatment of cancer that are now in clinical trials.

Key concepts

A major mechanism by which mammalian cells kill themselves involves members of the BCL‐2 family of proteins, some of which
promote cell death, and others which inhibit cell death.

BCL‐2 family proteins interact with each other to regulate and implement the cell death programme.

Abnormalities to the regulation of this cell death process, including mutations to genes for BCL‐2 family members, can lead
to a disease, such as cancer.

Keywords: BCL‐2; BCLX; MCL1; BAX; BAK; BH3‐only

Figure 1.

There are three classes of BCL‐2 family proteins: Antiapoptotic family members (top, blue symbol); BAX, BAK and Bok (middle, purple symbol) and BH3‐only proteins (top, green symbol). All BCL‐2 family members bear a number of BCL‐2
homology (BH) motifs. Although all have a BH3 motif (green), antiapoptotic BCL‐2 family members and the proapoptotic proteins
BAX, BAK and Bok, all bear a BH1 (yellow), a BH2 (blue), a BH3 (green) and a BH4 (red) motif. Most BCL‐2 family members also have a hydrophobic region at the carboxy‐terminus (grey) that can act as a transmembrane
domain. When antiapoptotic BCL‐2 family members and the proapoptotic multiple BH motif containing proteins fold, the BH3, BH1 and BH2 motifs form a hydrophobic pocket (depicted as indentations in the diagrams on the right) that is capable of binding to the
BH3 α helices (depicted as fingers) of other BCL‐2 family members.

Figure 2.

Complex of Bcl‐x (blue) with the BH3 helix peptide from BAK (red). The BAX BH3 peptide fits into a hydrophobic groove on the surface of Bcl‐x. The BH3 of Bcl‐x itself is coloured green. Note that
Bcl‐x, like all multidomain BCL‐2 family members, is almost entirely composed of α helices. BCL‐2 antagonist compounds were
designed to occupy the same groove as the BAK peptide shown here. Structure from 1bxl drawn using Polyview‐3D http://polyview.cchmc.org/.

Figure 3.

In this model, BAX and BAK (purple) are depicted as existing in 3 states. In healthy cells, they exist as monomers in the cytoplasm (BAX) or on mitochondria (BAK) in an inactive state. They spontaneously adopt a ‘ready’ conformation (BH3 ‘fingers’ exposed), which allows them to bind
to BCL‐2, MCL1 or BCLX (blue), but doing so promotes their reversion into the inactive state (BH3 not exposed). BH3‐only proteins (green) can bind
to BCL‐2, MCL1 and BCLX, preventing them from inactivating BAX and BAK. Some BH3‐onlys, such as BIM, PUMA and tBID can also interact with BAX and BAK on the mitochondria (pink) to increase the rate at which they adopt the active conformation (middle panel) that somehow makes
the outer membrane permeable, so that cytochrome c (red) is released (right panel). Artificial BCL‐2 antagonists, such as
ABT‐263 (light blue) can act like BH3‐only proteins by binding to antiapoptotic BCL‐2 family proteins. According to this model,
apoptosis can be triggered by increasing the concentration of BH3‐only proteins, adding an artificial BCL‐2 antagonist, or
depleting the cells of antiapoptotic BCL‐2 family members. Although BAX and BAK can spontaneously activate to allow mitochondrial membrane permeability, this might be accelerated by the presence of certain
BH3‐only proteins on the mitochondrial outer membrane. In healthy (non‐apoptotic) cells, only small amounts of antiapoptotic
BCL‐2 members need to be bound to BAX and BAK at any one time.

Del Gaizo Moore V and
Letai A
(2008)
Rational design of therapeutics targeting the BCL‐2 family: are some cancer cells primed for death but waiting for a final push?
Advances in Experimental Medicine and Biology
615:
159–175.